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Granulosa Cell Survival and Proliferation Are Altered in Polycystic Ovary Syndrome

Academic Department of Women’s Health (M.D., O.D., B.H., E.S.), Barts and The London, Queen Mary’s School of Medicine, University of London, London E1 1BB, United Kingdom; Institute of Cell and Molecular Sciences (M.I., L.G., A.S.), Queen Mary’s School of Medicine, London E1 2AT, United Kingdom; and Newham University Hospital National Health Service Trust (O.D., M.R.), London E13 8SL, United Kingdom

Address all correspondence and requests for reprints to: Professor O. Djahanbakhch, Academic Department of Obstetrics and Gynaecology, Barts and The London, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom. E-mail: o.b.djahanbakhch{at}qmul.ac.uk.

Context: Polycystic ovary syndrome (PCOS) represents the most common endocrine abnormality in women of reproductive age. The cause of PCOS remains largely unknown, but studies suggest an intrinsic ovarian abnormality.

Objective: The objective of the study was to test our hypothesis that differences in granulosa cell proliferation and apoptosis may underlie abnormalities that affect follicular development.

Design: Granulosa cells were prepared from follicular fluid aspirated from 4- to 8-mm follicles of unstimulated ovaries during routine laparoscopy or laparotomy from women with anovulatory PCOS and those with regular ovulatory cycles.

Setting: The study was conducted at a university hospital.

Patients: Fourteen women with anovulatory PCOS and nine women with regular ovulatory cycles participated in the study.

Main Outcome Measures: Immunocytochemistry on granulosa cells to investigate apoptotic and proliferation rates, together with real-time RT-PCR to analyze gene expression profiles of apoptotic regulators, was measured.

Results: Significantly lower apoptotic rates were found in granulosa cells from patients with PCOS, compared with women with regular ovulatory cycles (P = 0.004). Lower apoptotic rates were associated with decreased levels of the apoptotic effector caspase-3 (P = 0.001) and increased levels of the anti-apoptotic survival factor cellular inhibitor of apoptosis proteins-2 in the PCOS group that were coupled to higher proliferation rates (P = 0.032). Gene expression profiling confirmed the immunocytochemical findings.

Conclusions: Our findings indicate that there are significant differences in the rate of cell death and proliferation in granulosa cell populations in PCOS patients. These are associated with decreased expression of apoptotic effectors and increased expression of a cell survival factor. These results provide new insights that may be useful in developing specific therapeutic intervention strategies in PCOS.